This proposal focuses on the synthesis and biological evaluation of natural and unnatural quassinoids which display solid tumor selectivity. The major thrust of our program is the synthesis of quassinoid analogs for in vitro and in vivo studies in order to define the best candidate to move forward into the clinic. In addition this proposal concentrates on the total synthesis of scytophycin C and tolytoxin. The scytophycins and tolytoxins are solid tumor selective in vitro, however, despite being high priority candidates for in vivo evaluation, no material is available. A major effort will be devoted to probing the structural requirements for solid tumor activity. In part III of this grant application we propose to examine a number of Castela species (plants known to contain quassinoids) in hopes of finding a rich source of glaucarubolone and related quassinoids for our analog program and, more importantly, identifying novel cytotoxic quassinoids as well other natural products which will be solid tumor selective.